Articles www.thelancet.com Vol 368 October 14, 2006 1349 Efficacy, safety, and tolerability of amodiaquine plus sulphadoxine-pyrimethamine used alone or in combination for malaria treatment in pregnancy: a randomised trial Harry Tagbor, Jane Bruce, Edmund Browne, Anna Randal, Brian Greenwood, Daniel Chandramohan Summary Background The widespread increase in resistance of Plasmodium falciparum to chloroquine and sulphadoxine-pyrimethamine threatens the use of these drugs for malaria treatment in pregnancy. We aimed to assess the safety and efficacy of amodiaquine alone or in combination with sulphadoxine-pyrimethamine as alternative regimens. Methods Pregnant women with a gestational age of 16 weeks or more who attended antenatal clinics at a district hospital in Ghana were screened for malaria with OptiMAL dipsticks. 900 pregnant women who had a positive test result and P falciparum asexual stage parasitaemia were enrolled and randomly assigned chloroquine, sulphadoxine-pyrimethamine, amodiaquine, or amodiaquine plus sulphadoxine-pyrimethamine. The primary outcome was parasitological failure by day 28 of treatment. Women were seen on days 3, 7, 14, and 28 after the start of treatment to assess the effect of treatment on peripheral parasitaemia, haemoglobin concentration, white-blood-cell count, and liver function. Additionally, reports of adverse effects were solicited and monitored during follow-up visits. Analysis was by intention to treat. This trial is registered with the US National Institute of Health clinical trials database number NCT00131703. Findings PCR-corrected parasitological failure by day 28 was 14%, 11%, 3%, and 0% in the women assigned chloroquine, sulphadoxine-pyrimethamine, amodiaquine, and amodiaquine plus sulphadoxine-pyrimethamine, respectively (p<0·0001). No serious liver toxic effects or white-blood-cell dyscrasias were noted. Minor side-effects were reported more often on day 3 by women receiving amodiaquine (86%) or amodiaquine plus sulphadoxine-pyrimethamine (90%) than those receiving sulphadoxine-pyrimethamine (48%) or no antimalarial drugs (34%; p<0·0001 for every comparison). Interpretation Amodiaquine alone or in combination with sulphadoxine-pyrimethamine, although associated with minor side-effects, is effective when used to treat malaria in pregnancy. Introduction Plasmodium falciparum infection in pregnancy is associated with maternal and perinatal morbidity. 1–3 For malaria control in pregnancy, WHO recommends the use of insecticide-treated bednets, intermittent preventive treatment with sulphadoxine-pyrimethamine in the second and third trimesters, and prompt and effective treatment of malaria and anaemia. 1,4 Chloroquine and sulphadoxine-pyrimethamine are the safest and most readily available and affordable drugs for the treatment or prevention of uncomplicated malaria in pregnancy in most African countries. However, these drugs are becoming ineffective against uncompleted malaria in many areas because of increasing parasite resistance. Therefore, alternative safe and efficacious antimalarial drugs are needed urgently for both treatment of malaria during pregnancy and intermittent preventive treatment. Most countries in Africa are adopting artesunate-based combination therapy (ACT) as the preferred drug for the treatment of uncomplicated malaria. However, very little information on the safety of ACT during pregnancy is available, and there are concerns about the possible teratogenicity of these drugs when given in the first trimester of pregnancy. 5 In Ghana, chloroquine was the preferred treatment for uncomplicated malaria in children and pregnant women, until a decision was made to change to the combination of artesunate and amodiaquine. Since amodiaquine is effective in some areas with chloroquine resistance, 6,7 and because the extent of resistance to sulphadoxine-pyrimethamine in west Africa is not as high as that in east Africa, 7–9 we postulated that amodiaquine, used either alone or in combination with sulphadoxine-pyrimethamine, might be a safe and efficacious drug option for malaria treatment in pregnancy and for intermittent preventive treatment in Ghana until the safety of ACTs in pregnancy has been established. However, little information exists about the safety or efficacy of amodiaquine in pregnancy. A review 10 found only six reports on the use of amodiaquine in pregnancy, of which four described its use for chemoprophylaxis and two for treatment. Toxic effects were assessed specifically in only one of the chemoprophylaxis studies, and none reported the outcome of pregnancy. The two treatment studies, one in Lancet 2006; 368: 1349–56 See Comment page 1306 St Theresa’s Hospital, Nkoranza, Ghana (H Tagbor DrPH); Department of Community Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana (E Browne PhD); and Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK (J Bruce MSc, A Randall MSc, Prof B Greenwood MD, D Chandramohan PhD) Correspondence to: Dr Harry Tagbor, St Theresa’s Hospital, PO Box 30, Nkoranza–B/A, Ghana Harry.Tagbor@lshtm.ac.uk